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The Management of Sepsis Christine A. Zawistowski, MD
Management of sepsis in the pediatric patient is guideline driven. The treatment occurs in two phases, the first hour being the most crucial. Initial treatment consists of timely recognition of shock and interventions aimed at supporting cardiac output and oxygen delivery along with administration of antibiotics. The mainstay of treatment for this phase is fluid resuscitation. For patients in whom this intervention does not reverse the shock medications to support blood pressure should be started
and respiratory support may be necessary. Differentiation between warm and cold shock and risk factors for adrenal insufficiency will guide further therapy. Beyond the first hour of treatment patients may require intensive care unit care where invasive monitoring may assist with further treatment options should shock not be reversed in the initial hour of care. Curr Probl Pediatr Adolesc Health Care 2013;43:285-291
Introduction
The seminal study for early goal-directed therapy was published in 2001.4 Adult patients with septic uidelines were developed for the management shock were randomized upon presentation to the of sepsis when it was noted that mortality from emergency department to early goal-directed therapy sepsis had not improved in a decade. Pediatric or conventional therapy. Those in the study arm had specific guidelines first appeared in 2002.1 These were arterial and central venous catheters placed for monthen updated in 2007 and again in 2013.2,3 The general itoring. Therapeutic goals for treatment included mainprinciples of resuscitation follow those of the pediatric taining the central venous pressure, mean arterial advanced life-support program. pressure, and superior vena cava saturations within specific parameters. In-hospital mortality was signifiBackground—Early Goal-Directed cantly less in the goal-directed therapy group (30.5% Therapy vs. 46.5%, p ¼ 0.0009). This was the first large-scale study that showed a reduction in mortality from sepsis Resuscitation should commence in the emergency deand demonstrated the importance of early recognition partment once sepsis is suspected. The mainstay of initial and aggressive resuscitation. therapy is early aggressive treatment to restore the balance 4 Further studies continued to between oxygen delivery and demand. show the benefits of early recogEarly therapy aims to improve preload, The mainstay of initial nition and aggressive treatment afterload, and contractility. This is therapy is early aggressive of sepsis. A meta-analysis of 21 accomplished through the use of fluids, randomized controlled trials of treatment to restore the vasoactive substances, oxygen, antibiotics, and optimization of ventilation. balance between oxygen sepsis showed a 23% mortality difference between control and Targeted end points look for improvedelivery and demand. protocol groups in severely ill ment in perfusion, taking into account patients (control group patients vital signs, examination findings, and with 420% mortality) when laboratory findings. Early studies showed the survival patients with acute critical illness are treated early to benefit of early aggressive fluid resuscitation, which was 4,5 achieve goals prior to organ failure.6 A retrospective also found to be true in adult patients. analysis of 91 infants and children showed a greater than 9-fold increased odds of survival with prompt recogniFrom the Department of Pediatrics, Division of Pediatric Critical Care, NYU School of Medicine, New York, NY. tion and treatment of shock.7 In 2002 the first pediatric Curr Probl Pediatr Adolesc Health Care 2013;43:285-291 guidelines for the management of pediatric and neonatal 1538-5442/$ - see front matter patients in septic shock were published.1 The guidelines & 2013 Mosby, Inc. All rights reserved. were time based with the first 60 min being the most http://dx.doi.org/10.1016/j.cppeds.2013.10.005
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crucial. Goals and parameters were defined by both clinical and oxygen-utilization variables. Goals of therapy included capillary refill less than 2 s, urine output of at least 1 mL/kg/h, normal pulses without a differential between peripheral and central pulses, a mixed venous oxygen saturation greater than 70%, declining lactate and base deficit, and an improved level of consciousness. The guidelines were developed from the best data available and many recommendations are expert consensus of that data due to the small numbers of studies and small sample sizes within the studies. Data collected as a result of the 2002 guidelines demonstrated that they were useful, effective, and caused no evidence of harm.2 The guidelines were updated in 2007 and again in 2013 and have remained largely unchanged due to lack of new evidence to the contrary.
Management (Tables 1 and 2) The management of sepsis is divided into that for the first hour and then subsequent care. The initial hour of resuscitation often occurs in the emergency department, as that is often the entry point into the healthcare system for patients in septic shock.
Time 0–5 min The timeline for treatment starts in the first 5 min with the recognition of shock and should ideally be prior to the onset of hypotension. Clinical signs of shock include an alteration of body temperature with hypothermia or hyperthermia, alteration in mental status, and peripheral vasodilation (warm shock) or
TABLE 1. Algorithm for time sensitive goal-directed, stepwise management of shock in infants and children2
Time Recognition 0–5 min
Shock not reversed Initial resuscitation 5–15 min
Shock not reversed Fluid-refractory shock 15–60 min
Shock not reversed Catecholamine-resistant shock 460 min Pediatric Intensive Care Unit Monitor CVP, SCVO2470% Cold shock with normal BP 1. Titrate fluid and epinephrine SVCO2 470% and Hgb 410 g/dL 2. SVCO2 o70%, add vasodilator with fluid loading, consider levosimendan
Shock not reversed Persistent catecholamine-resistant shock
Shock not reversed Refractory shock
Intervention 1. Recognize shock: decreased mental status and perfusion 2. Begin high-flow oxygen 3. Establish IV/IO access
1. Push boluses of 20 ml/kg isotonic saline or colloid 460 ml/kg until perfusion improves or rales or hepatomegaly develop 2. Correct hypoglycemia 3. Correct hypocalcemia 4. Start antibiotics
1. 2. 3. 4.
Begin inotrope via IV/IO Obtain central access and airway if needed Cold shock: titrate dopamine, if resistant titrate epinephrine Warm shock: titrate norepinephrine
Begin hydrocortisone if at risk for adrenal insufficiency
Cold shock with low BP 1. Titrate fluid and epinephrine SVCO2 470% and Hgb 410 g/dL 2. BP still low, consider norepinephrine 3. SVCO2 o70%, consider milrinone or levosimendan
Warm shock with low BP 1. Titrate fluid and norepinephrine SCVO2 470% 2. BP still low, consider vasopressin 3. SCVO2 o70%, consider low-dose epinephrine
1. Rule out/correct: pericardial effusion, pneumothorax, and elevated intra-abdominal pressure 2. Consider advanced monitoring tools to guide therapy with goal CI 43.3 and o6.0 L/min/m2
ECMO
CI, cardiac index.
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TABLE 2. Medications used to treat shock
Agent
Clinical effect
Dose
Dopamine
Increased cardiac output, increased inotropic effects, increased heart rate, and arterial vasoconstriction Increased heart rate, decreased stroke volume, and increased cardiac output Vasoconstriction and increased mean arterial pressure Increased myocardial contractility, increased venous and arterial dilation, decreased preload, and decreased systemic vascular resistance Increased systemic vascular resistance and vasoconstriction Suppress production of cytokines; increase sensitivity of the cardiovascular system to catecholamines, improving contractility, stroke volume, and systemic vascular resistance; replace insufficient endogenous steroids Increase blood calcium level Increase blood calcium level Increase blood glucose level
2 mcg/kg/min titrated up to 10 mcg/kg/min
Epinephrine Norepinephrine Milrinone
Vasopressin Hydrocortisone
Calcium chloride Calcium gluconate Dextrose
constriction (cold shock). Heart rates outside the normal range are a good early indicator of shock. Threshold heart rates found to be associated with an increased mortality in critically ill infants were less than or equal to 90 beats per minute (bpm) or more than 160 bpm; in critically ill children, they were found to be less than 70 bpm or greater than 150 bpm.8 Within the first 5 min after recognition of shock, highflow oxygen via a face mask should be started and intravenous or intraosseous access obtained. For patients who do not maintain oxygen saturations 494% on high-flow face mask oxygen and/or exhibit increased work of breathing high-flow nasal cannula (HFNC) or nasopharyngeal continuous positive airway pressure (CPAP) should be instituted to increase functional residual capacity and decrease work of breathing.
Time 5–15 min The next 10 min of management (time 5 min through 15 min) is aimed at restoration of normal mental status, threshold heart rates, peripheral perfusion (capillary refill o2 s), palpable distal pulses, and normal blood pressure for age. The mainstay therapy for this stage of resuscitation is fluid administration done as a push over 5-min intervals. Isotonic saline or colloid in aliquots of 20 mL/kg is rapidly administered manually. Emergency medicine research has shown that this can be done either through a peripheral intravenous catheter or central venous catheter.9 Fluid is administered up to or more than 60 mL/kg. Initial therapy usually requires 40–60 mL/kg but can be as much as 200 mL/kg.5
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0.05 mcg/kg/min titrated up to 1 mcg/kg/min 0.05–1 mcg/kg/min 0.5–1 mcg/kg/min
0.03–2 mU/kg/min 2–50 mg/kg/d
10 mg/kg 100 mg/kg 2–4 mL/kg; 12.5% dextrose if o2 months, 2–4 mL/kg; 25% dextrose if 42 months
There has traditionally been a concern that large volumes of fluid resuscitation for acute stabilization increase the incidence of acute respiratory distress syndrome, but this has shown to not be the case.5,10 Likewise, there is no correlation between large volumes of fluid resuscitation and cerebral edema.5,11 There is also no difference in the efficacy of crystalloids (normal saline, and Lactated Ringer's) vs. colloids (dextran, gelatin, and 5% albumin) as the choice of fluid for acute volume resuscitation.12–14 After each administered bolus, the patient should be assessed for improvement in perfusion, rales, increased work of breathing, hypoxemia, and hepatomegaly. During this stage of resuscitation glycemic status and calcium status should be checked and corrected to maintain metabolic homeostasis. Hypoglycemia can cause neurologic damage when missed. Glucose infusion rates of 6–8 mg/kg/min in newborns or 4–6 mg/kg/min in non-newborns should be targeted. This need can often be met by providing 10% dextrose in addition to saline as maintenance intravenous fluids. Patients with liver failure require higher glucose infusion rates to meet the body's needs. Conversely, hyperglycemia should be avoided as well, as levels 4140 mg/dL were found to be a risk factor for mortality.15 Hypocalcemia, defined as an ionized calcium o1.025 mmol/L or total serum calcium o8.5 mg/dL, should also be quickly identified and corrected as it is a frequent contributor of reversible cardiac dysfunction.16,17 Calcium can be repleted either using calcium chloride at a dose of 10 mg/kg or calcium gluconate at a dose of 100 mg/kg. Centrallined administration is preferred for calcium chloride
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as extravasation of calcium can result in severe necrosis and tissue sloughing. Both preparations can be given as an intravenous push over 3–5 min or as an infusion over 1-h. The goal of therapy should be to maintain a normal ionized calcium concentration via intravenous calcium supplementation. The final cornerstone of this stage of resuscitation is administration of broad-spectrum antibiotics once appropriate cultures have been obtained. The initial antibiotics should be broad enough to cover the most likely pathogens and have adequate penetration into the presumed primary source of infection. Clinicians should be aware of specific susceptibility patterns in the community and institution to help guide initial therapy. Possible combinations of antibiotics include an extended spectrum penicillin or third- or fourth-generation cephalosporin or carbapenem ⫾ aminoglycoside ⫾ vancomycin. At the end of the initial 15-min period, if shock is not reversed a second peripheral intravenous catheter should be inserted and inotrope therapy started.
fold. Fluid-refractory shock is best managed with invasive hemodynamic monitoring, which in an uncooperative potentially coagulopathic patient is best accomplished by sedation and immobilization, requiring intubation and mechanical ventilation for optimal control. Intubation and mechanical ventilation is also an important intervention for any patient whose cardiovascular function is not rapidly stabilized with fluid and inotropes. Up to 40% of cardiac output may be needed to support the work of breathing and this can be unloaded by providing mechanical ventilation. In addition, the increased intrathoracic pressure provided by mechanical ventilation reduces left ventricular afterload, which may be beneficial to patients with a low cardiac index and high systemic vascular resistance. In patients with elevated pulmonary vascular resistance, ventilator-controlled mild hyperventilation can compensate for metabolic acidosis. Finally, in any patient with evidence of respiratory failure or impaired mental status, there should be no hesitation to proceed with intubation and the initiation of mechanical ventilation.
Time 15–60 min At time point 15 min, if shock is not reversed it is considered to be fluid refractory and inotropes should be started. The original guidelines published in 2002 recommended obtaining central venous access prior to starting therapy. It was found that mortality increased with delay in time to inotropic use due to lack of central venous access and subsequent guidelines recommended beginning this therapy via an intravenous or intraosseous catheter. Medications should be titrated to maintain adequate perfusion. At this point, central venous access and if needed, an airway, should be obtained. Ketamine and atropine are the recommended agents to use for sedation for these procedures. Ketamine is a central N-methyl-D-aspartate (NMDA) receptor blocker, which blocks nuclear factor κB transcription and reduces systemic interleukin-6 production. Ketamine does not affect the adrenal axis or cardiovascular stability, making it an ideal agent for use in patients in shock.18 Atropine is a competitive antagonist of the muscarinic acetylcholine receptor. It is administered prior to intubation for one of two reasons: either to block the action of the vagus nerve, which can be stimulated with direct laryngoscopy, especially in small infants or to counteract the sialogogue action of ketamine through its direct antimuscarinic action. Indications for intubation and mechanical ventilation in a patient in shock are several
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Cold Shock Cold shock is a consequence of poor cardiac output and is evidenced by poor peripheral perfusion with cool extremities, delayed capillary refill, and diminished or absent peripheral pulses. Low cardiac output (cold shock) has been shown to be associated with mortality in pediatric patients.19,20 Vasoactive agents suitable for the treatment of cold shock include dopamine and epinephrine administered into the central circulation.21 The dosing range for dopamine should fall within 5–9 mcg/kg/min; at this dose, it works as an inotrope to improve contractility.22 In instances when dopamine is ineffective, epinephrine in a dosing range of 0.05–0.3 mcg/kg/min should be used; in this dosing range, it acts predominantly as a β-adrenergic agonist with a resulting increase in heart rate and stroke volume. It should be noted that epinephrine stimulates gluconeogenesis and glycogenolysis and inhibits the action of insulin, leading to an increase in blood glucose. Epinephrine also promotes increased delivery of lactate to the liver (to be used as a substrate for glucose production), with a resulting increase in blood lactate concentration.
Warm Shock Warm shock is caused by low systemic venous resistance. Patients in this state appear overly well
Curr Probl Pediatr Adolesc Health Care, November/December 2013
perfused, with flash capillary refill, bounding peripheral pulses, and a flushed appearance. The vasoactive agent of choice for this state is centrally administered norepinephrine in a dosing range of 0.05–1 mcg/kg/min. Norepinephrine is a potent β-adrenergic agonist, which increases mean arterial pressure as a result of vasoconstriction with little change in heart rate.
pressure, cardiac output, and maintaining oxygen carrying capacity. At this point, the patient should be in an intensive care unit and invasive monitoring should guide further treatment. If not already done, a central venous catheter should be placed and a central venous pressure (CVP) recorded and trended. The optimal CVP for each patient will be dictated by their clinical condition. Although a CVP of 5–10 cm H2O is Time 60 min considered within normal range, some patients may require higher levels to maintain cardiac output. The first 60 min after the recognition of shock is Observing the relationship between the CVP and blood considered the “golden hour” during which time therapressure (i.e., when the CVP is 18 cm H2O, the patient pies need to be initiated to reverse the shock. Carcillo has normal BP for age, when it drops to 12 cm H2O the et al.5 showed an improved survival patient becomes hypotensive) in patients receiving 440 mL/kg of will guide the clinician as to what fluid in the first hour of treatment in a CVP a patient requires. Vasoacgroup of 34 patients presenting to the The first 60 minutes after tive agents and fluid should be emergency department in shock. Han the recognition of shock is titrated to maintain a normal et al.7 have shown that for every mean arterial pressure (MAP) considered the “golden additional hour of persistent shock, CVP, which range between 55 for hour” during which time there is a 42-fold increased odds of a term newborn and 65 for therapies need to be mortality in pediatric patients with patients who are 2 years of age septic shock. At time point 60 min, if initiated to reverse and older. Mixed venous oxygen the patient does not have evidence of the shock. saturation (SCVO2), an indirect reversal of shock, they fall into the indicator of the adequacy of carcategory of having catecholaminediac output to meet tissue metaresistant shock and hydrocortisone therapy should be bolic demand, should be checked periodically with a initiated if the patient is at risk for absolute adrenal goal of maintaining saturations 470%. Normal arterial insufficiency. A patient with purpura fulminans and oxygen saturation is 100% and mixed venous saturaWaterhouse–Friderichsen syndrome, one who has pretion is 470%. In concert with maintenance of cardiac viously received steroid therapies for chronic illness and output, hemoglobin concentration is an important one with pituitary or adrenal abnormalities are all at risk determinant of oxygen delivery. Maintaining a hemofor adrenal insufficiency. A peak cortisol concentratioglobin concentration 410 g/dL is of utmost imporn o18 mcg/dL obtained after corticotropin stimulation tance in a patient in shock.4,23 For patients with a is indicative of adrenal insufficiency. This test may be SCVO2 o70% adding a vasodilator with fluid loading helpful to perform in centers with the capability to obtain can improve oxygen delivery. Agents that can be used results in a timely fashion (i.e., 30 min or less) but in are nitrovasodilators, such as sodium nitroprusside, patients with catecholamine-resistant shock and risk nitroglycerine, and milrinone. The nitrovasodilators factors for adrenal insufficiency, steroids should not be recruit microcirculation and reduce ventricular afterwithheld due to lack of results. The dose of steroid can load, which allows better ventricular ejection and be titrated over a wide dosing range to achieve resolution overall improvement in cardiac output. Milrinone of shock, using between 2 and 50 mg/kg/d of hydroimproves contractility and lowers systemic vascular cortisone given as a continuous infusion or via interresistance by inhibiting type III phosphodiesterase, mittent dosing. The hydrocortisone should be weaned off which in turn increases intracellular cAMP by blocking as tolerated to minimize toxicity. its hydrolysis. It is not receptor mediated and is useful if adrenergic receptors are down regulated or desensitized. Because normal renal function is needed for Beyond the First Hour milrinone clearance, the dose should be lowered in patients with signs of renal insufficiency. Milrinone Beyond the first hour of treatment, the treatment goal has a long half-life compared to the other medications is to improve oxygen delivery by supporting blood
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and o6.0 L/min/m2, which has been associated with used to support blood pressure ( mean half-life 2.3 h) and can cause hypotension, which can be treated with the best outcomes in septic shock patient.22 For those norepinephrine or vasopressin. An alternative agent to patients not aided by these tools, extracorporeal consider is levosimendan, which exerts a positive membrane oxygenation (ECMO) should be considinotropic effect by increasing calcium sensitivity of ered. Survival rates in septic shock patients placed on myocytes by binding to cardiac troponin C in a ECMO are 73% for newborns and 39% for older calcium-dependent manner. It also has a vasodilatory children.26 effect by opening adenosine-triphosphate-sensitive Guidelines for the management of shock in children potassium channels in vascular smooth muscle. Thus, have been in effect for the last 10 years. They are time in the endotoxin-induced heart dysfunction of septic based and can be enacted in whatever setting shock is shock, levosimendan treats the first recognized. The interventions source of the problem.24 In are designed to quickly improve oxygen delivery through mainteinstances where these measures All practitioners who care nance of cardiac output and timely are not successful, vasopressin for pediatric patients are administration of antibiotics. Since should be added. Vasopressin is the original guidelines were puba peptide hormone that increases encouraged to become lished, two revisions have been peripheral vascular resistance via familiar with these made, but the content has remained the V1 receptors found on vasguidelines as they are clear, largely unchanged. Many studies cular smooth muscle of the systemic circulation. It has been concise and can save lives. have tested the recommendations of the original guidelines. There is shown to increase systemic vasample evidence that the guidelines cular resistance, mean arterial 25 are effective and do not cause harm.7,27–31 All practiblood pressure, and urine output in septic shock. There are some instances in which the patient remains tioners who care for pediatric patients are encouraged in shock despite all of the aforementioned intervento become familiar with these guidelines as they are tions. After initial assessment for correctable causes, clear, concise, and can save lives. such as pericardial effusions, pneumothoraces, and intra-abdominal hypertension, more advanced tools must be employed to guide therapy. Pulmonary artery References (PA) catheters can assist in the identification of 1. Carcillo JA, Fields AI, American College of Critical Care selective left ventricular dysfunction and can determine Medicine Task Force Committee Members. Clinical practice the relative contribution of right and left ventricular parameters for hemodynamic support of pediatric and neonatal work. The measured and derived values that are patients in septic shock. Crit Care Med 2002;30(6):1365–78. 2. Brierley J, Carcillo JA, Choong K, et al. Clinical practice obtained can allow the clinician to titrate medications parameters for hemodynamic support of pediatric and neonatal and interventions that affect preload, afterload, and septic shock: 2007 update from the American College of contractility and follow-up with subsequent PA cathCritical Care Medicine. Crit Care Med 2009;37(2):666–88. eter measurements to assess the effects of treatment. 3. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis Pulse index contour cardiac output catheters (PICCO) campaign: international guidelines for management of severe estimate global end-diastolic volume in the heart, sepsis and septic shock: 2012. Crit Care Med 2013;41(2): 580–637. extravascular lung water, and assess adequacy of 4. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed preload. PICCO catheters were developed as a lesstherapy in the treatment of severe sepsis and septic shock. invasive way to obtain much of the same information N Engl J Med 2001;345(19):1368–77. that PA catheters provide. The measurements from a 5. Carcillo JA, Davis AL, Zaritsky A. Role of early fluid PICCO catheter allow the clinician to assess cardiac resuscitation in pediatric septic shock. J Am Med Assoc 1991;266(9):1242–5. function and volume status and titrate therapies accord6. Kern JW, Shoemaker WC. Meta-analysis of hemodynamic ingly. Follow-up measurements are then obtained to optimization in high-risk patients. Crit Care Med 2002;30(8): evaluate treatment. Femoral artery thermodilution 1686–92. catheters and Doppler ultrasound can also aid in the 7. Han YY, Carcillo JA, Dragotta MA, et al. Early reversal of assessment of cardiac output. These devices can help pediatric-neonatal shock by community physicians is associguide therapy to achieve a goal cardiac index of 43.3 ated with improved outcome. Pediatrics 2003;112(4):793–9. 290
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8. Pollack MM, Ruttimann UE, Getson PR. Pediatric risk of mortality (PRISM) score. Crit Care Med 1988;16(11):1110–6. 9. Stoner MJ, Goodman DG, Cohen DM, et al. Rapid fluid resuscitation in pediatrics; testing the ACCM guidelines. Crit Care Med 2005;33:A68. 10. Zadrobilek E, Hackl W, Sporn P, Steinbereithner K. Effect of large volume replacement with balanced electrolyte solutions on extravascular lung water in surgical patients with sepsis syndrome. Intensive Care Med 1989;15(8):505–10. 11. Powell KR, Sugarman LI, Eskenazi AE, et al. Normalization of plasma arginine vasopressin concentrations when children with meningitis are given maintenance plus replacement fluid therapy. J Pediatr 1990;117(4):515–22. 12. Ngo NT, Cao XT, Kneen R, et al. Acute management of dengue shock syndrome: a randomized double-blind comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis 2001;32(2):204–13. 13. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomized controlled trials. Br Med J 1998;317(7153):235–40. 14. Oca MJ, Nelson M, Donn SM. Randomized trial of normal saline versus 5% albumin for the treatment of neonatal hypotension. J Perinatol 2003;23(6):473–6. 15. Lin JC, Carcillo JA. Increased glucose/glucose infusion rate ratio predicts anion gap acidosis in pediatric sepsis. Crit Care Med 2004;32(suppl 20):A5. 16. Cardenas-Rivero N, Chernow B, Stoiko MA, Nussbaum SR, Todres ID. Hypocalcemia in critically ill children. J Pediatr 1989;114(6):946–51. 17. Roberton NR, Smith MA. Early neonatal hypocalcaemia. Arch Dis Child 1975;50(8):604–9. 18. Yli-Hankala A, Kirvelä M, Randell T, Lindgren L. Ketamine anaesthesia in a patient with septic shock. Acta Anaesthesiol Scand 1992;36(5):483–5. 19. Pollack MM, Fields AI, Ruttimann UE. Sequential cardiopulmonary variables of infants and children in septic shock. Crit Care Med 1984;12(7):554–9. 20. Pollack MM, Fields AI, Ruttimann UE. Distributions of cardiopulmonary variables in pediatric survivors and nonsurvivors of septic shock. Crit Care Med 1985;13(6):454–9. 21. Perkin RM, Levin DL. Shock in the pediatric patient. Part II. Therapy. J Pediatr 1982;101(3):319–32.
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22. Ceneviva G, Pashcal JA, Eckstein J, et al. Hemodynamic support in fluid refractory pediatric septic shock. Pediatrics 1998;102:e19. 23. de Oliveira CF, de Oliveira DS, Gottschald AF, Moura JD, Costa GA, et al. ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation. Intensive Care Med 2008;34(6):1065–75. 24. Matejovic M, Krouzecky A, Radej J, Novak I. Successful reversal of resistant hypodynamic septic shock with levosimendan. Acta Anaesthesiol Scand 2005;49(1):127–8. 25. Liedel JL, Meadow W, Nachman J, Koogler T, Kahana MD. Use of vasopressin in refractory hypotension in children with vasodilatory shock: five cases and a review of the literature. Pediatr Crit Care Med 2002;3(1):15–8. 26. Skinner SC, Iocono JA, Ballard HO, et al. Improved survival in venovenous vs venoarterial extracorporeal membrane oxygenation for pediatric noncardiac sepsis patients: a study of the Extracorporeal Life Support Organization registry. J Pediatr Surg 2012;47(1):63–7. 27. Wills BA, Nguyen MD, Ha TL, et al. Comparison of the three fluid solutions for resuscitation in dengue shock. N Engl J Med 2005;353:877–89. 28. Maitland K, Pamba A, English M, et al. Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit. Clin Infect Dis 2005;40:538–45. 29. Ninis N, Phillips C, Bailey L, et al. The role of healthcare delivery on outcome of meningococcal disease in children: Case control study of fatal and non-fatal cases. Br Med J 2005;330:1475. 30. de Oliveira CF, de Oliveira DS, Gottschald AF, et al. ACCM/ PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation. Intensive Care Med 2008; 34:1065–75. 31. Karapinar B, Lin JC, Carcillo JA. ACCM guidelines use, correct antibiotic therapy, and immune suppressant withdrawal are associated with improved survival in pediatric sepsis, severe sepsis, and septic shock. Crit Care Med 2004; 32(12 suppl 3):A161.
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The Management of Sepsis Christine A. Zawistowski, MD
Management of sepsis in the pediatric patient is guideline driven. The treatment occurs in two phases, the first hour being the most crucial. Initial treatment consists of timely recognition of shock and interventions aimed at supporting cardiac output and oxygen delivery along with administration of antibiotics. The mainstay of treatment for this phase is fluid resuscitation. For patients in whom this intervention does not reverse the shock medications to support blood pressure should be started
and respiratory support may be necessary. Differentiation between warm and cold shock and risk factors for adrenal insufficiency will guide further therapy. Beyond the first hour of treatment patients may require intensive care unit care where invasive monitoring may assist with further treatment options should shock not be reversed in the initial hour of care. Curr Probl Pediatr Adolesc Health Care 2013;43:285-291
Introduction
The seminal study for early goal-directed therapy was published in 2001.4 Adult patients with septic uidelines were developed for the management shock were randomized upon presentation to the of sepsis when it was noted that mortality from emergency department to early goal-directed therapy sepsis had not improved in a decade. Pediatric or conventional therapy. Those in the study arm had specific guidelines first appeared in 2002.1 These were arterial and central venous catheters placed for monthen updated in 2007 and again in 2013.2,3 The general itoring. Therapeutic goals for treatment included mainprinciples of resuscitation follow those of the pediatric taining the central venous pressure, mean arterial advanced life-support program. pressure, and superior vena cava saturations within specific parameters. In-hospital mortality was signifiBackground—Early Goal-Directed cantly less in the goal-directed therapy group (30.5% Therapy vs. 46.5%, p ¼ 0.0009). This was the first large-scale study that showed a reduction in mortality from sepsis Resuscitation should commence in the emergency deand demonstrated the importance of early recognition partment once sepsis is suspected. The mainstay of initial and aggressive resuscitation. therapy is early aggressive treatment to restore the balance 4 Further studies continued to between oxygen delivery and demand. show the benefits of early recogEarly therapy aims to improve preload, The mainstay of initial nition and aggressive treatment afterload, and contractility. This is therapy is early aggressive of sepsis. A meta-analysis of 21 accomplished through the use of fluids, randomized controlled trials of treatment to restore the vasoactive substances, oxygen, antibiotics, and optimization of ventilation. balance between oxygen sepsis showed a 23% mortality difference between control and Targeted end points look for improvedelivery and demand. protocol groups in severely ill ment in perfusion, taking into account patients (control group patients vital signs, examination findings, and with 420% mortality) when laboratory findings. Early studies showed the survival patients with acute critical illness are treated early to benefit of early aggressive fluid resuscitation, which was 4,5 achieve goals prior to organ failure.6 A retrospective also found to be true in adult patients. analysis of 91 infants and children showed a greater than 9-fold increased odds of survival with prompt recogniFrom the Department of Pediatrics, Division of Pediatric Critical Care, NYU School of Medicine, New York, NY. tion and treatment of shock.7 In 2002 the first pediatric Curr Probl Pediatr Adolesc Health Care 2013;43:285-291 guidelines for the management of pediatric and neonatal 1538-5442/$ - see front matter patients in septic shock were published.1 The guidelines & 2013 Mosby, Inc. All rights reserved. were time based with the first 60 min being the most http://dx.doi.org/10.1016/j.cppeds.2013.10.005
G
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285
crucial. Goals and parameters were defined by both clinical and oxygen-utilization variables. Goals of therapy included capillary refill less than 2 s, urine output of at least 1 mL/kg/h, normal pulses without a differential between peripheral and central pulses, a mixed venous oxygen saturation greater than 70%, declining lactate and base deficit, and an improved level of consciousness. The guidelines were developed from the best data available and many recommendations are expert consensus of that data due to the small numbers of studies and small sample sizes within the studies. Data collected as a result of the 2002 guidelines demonstrated that they were useful, effective, and caused no evidence of harm.2 The guidelines were updated in 2007 and again in 2013 and have remained largely unchanged due to lack of new evidence to the contrary.
Management (Tables 1 and 2) The management of sepsis is divided into that for the first hour and then subsequent care. The initial hour of resuscitation often occurs in the emergency department, as that is often the entry point into the healthcare system for patients in septic shock.
Time 0–5 min The timeline for treatment starts in the first 5 min with the recognition of shock and should ideally be prior to the onset of hypotension. Clinical signs of shock include an alteration of body temperature with hypothermia or hyperthermia, alteration in mental status, and peripheral vasodilation (warm shock) or
TABLE 1. Algorithm for time sensitive goal-directed, stepwise management of shock in infants and children2
Time Recognition 0–5 min
Shock not reversed Initial resuscitation 5–15 min
Shock not reversed Fluid-refractory shock 15–60 min
Shock not reversed Catecholamine-resistant shock 460 min Pediatric Intensive Care Unit Monitor CVP, SCVO2470% Cold shock with normal BP 1. Titrate fluid and epinephrine SVCO2 470% and Hgb 410 g/dL 2. SVCO2 o70%, add vasodilator with fluid loading, consider levosimendan
Shock not reversed Persistent catecholamine-resistant shock
Shock not reversed Refractory shock
Intervention 1. Recognize shock: decreased mental status and perfusion 2. Begin high-flow oxygen 3. Establish IV/IO access
1. Push boluses of 20 ml/kg isotonic saline or colloid 460 ml/kg until perfusion improves or rales or hepatomegaly develop 2. Correct hypoglycemia 3. Correct hypocalcemia 4. Start antibiotics
1. 2. 3. 4.
Begin inotrope via IV/IO Obtain central access and airway if needed Cold shock: titrate dopamine, if resistant titrate epinephrine Warm shock: titrate norepinephrine
Begin hydrocortisone if at risk for adrenal insufficiency
Cold shock with low BP 1. Titrate fluid and epinephrine SVCO2 470% and Hgb 410 g/dL 2. BP still low, consider norepinephrine 3. SVCO2 o70%, consider milrinone or levosimendan
Warm shock with low BP 1. Titrate fluid and norepinephrine SCVO2 470% 2. BP still low, consider vasopressin 3. SCVO2 o70%, consider low-dose epinephrine
1. Rule out/correct: pericardial effusion, pneumothorax, and elevated intra-abdominal pressure 2. Consider advanced monitoring tools to guide therapy with goal CI 43.3 and o6.0 L/min/m2
ECMO
CI, cardiac index.
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TABLE 2. Medications used to treat shock
Agent
Clinical effect
Dose
Dopamine
Increased cardiac output, increased inotropic effects, increased heart rate, and arterial vasoconstriction Increased heart rate, decreased stroke volume, and increased cardiac output Vasoconstriction and increased mean arterial pressure Increased myocardial contractility, increased venous and arterial dilation, decreased preload, and decreased systemic vascular resistance Increased systemic vascular resistance and vasoconstriction Suppress production of cytokines; increase sensitivity of the cardiovascular system to catecholamines, improving contractility, stroke volume, and systemic vascular resistance; replace insufficient endogenous steroids Increase blood calcium level Increase blood calcium level Increase blood glucose level
2 mcg/kg/min titrated up to 10 mcg/kg/min
Epinephrine Norepinephrine Milrinone
Vasopressin Hydrocortisone
Calcium chloride Calcium gluconate Dextrose
constriction (cold shock). Heart rates outside the normal range are a good early indicator of shock. Threshold heart rates found to be associated with an increased mortality in critically ill infants were less than or equal to 90 beats per minute (bpm) or more than 160 bpm; in critically ill children, they were found to be less than 70 bpm or greater than 150 bpm.8 Within the first 5 min after recognition of shock, highflow oxygen via a face mask should be started and intravenous or intraosseous access obtained. For patients who do not maintain oxygen saturations 494% on high-flow face mask oxygen and/or exhibit increased work of breathing high-flow nasal cannula (HFNC) or nasopharyngeal continuous positive airway pressure (CPAP) should be instituted to increase functional residual capacity and decrease work of breathing.
Time 5–15 min The next 10 min of management (time 5 min through 15 min) is aimed at restoration of normal mental status, threshold heart rates, peripheral perfusion (capillary refill o2 s), palpable distal pulses, and normal blood pressure for age. The mainstay therapy for this stage of resuscitation is fluid administration done as a push over 5-min intervals. Isotonic saline or colloid in aliquots of 20 mL/kg is rapidly administered manually. Emergency medicine research has shown that this can be done either through a peripheral intravenous catheter or central venous catheter.9 Fluid is administered up to or more than 60 mL/kg. Initial therapy usually requires 40–60 mL/kg but can be as much as 200 mL/kg.5
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0.05 mcg/kg/min titrated up to 1 mcg/kg/min 0.05–1 mcg/kg/min 0.5–1 mcg/kg/min
0.03–2 mU/kg/min 2–50 mg/kg/d
10 mg/kg 100 mg/kg 2–4 mL/kg; 12.5% dextrose if o2 months, 2–4 mL/kg; 25% dextrose if 42 months
There has traditionally been a concern that large volumes of fluid resuscitation for acute stabilization increase the incidence of acute respiratory distress syndrome, but this has shown to not be the case.5,10 Likewise, there is no correlation between large volumes of fluid resuscitation and cerebral edema.5,11 There is also no difference in the efficacy of crystalloids (normal saline, and Lactated Ringer's) vs. colloids (dextran, gelatin, and 5% albumin) as the choice of fluid for acute volume resuscitation.12–14 After each administered bolus, the patient should be assessed for improvement in perfusion, rales, increased work of breathing, hypoxemia, and hepatomegaly. During this stage of resuscitation glycemic status and calcium status should be checked and corrected to maintain metabolic homeostasis. Hypoglycemia can cause neurologic damage when missed. Glucose infusion rates of 6–8 mg/kg/min in newborns or 4–6 mg/kg/min in non-newborns should be targeted. This need can often be met by providing 10% dextrose in addition to saline as maintenance intravenous fluids. Patients with liver failure require higher glucose infusion rates to meet the body's needs. Conversely, hyperglycemia should be avoided as well, as levels 4140 mg/dL were found to be a risk factor for mortality.15 Hypocalcemia, defined as an ionized calcium o1.025 mmol/L or total serum calcium o8.5 mg/dL, should also be quickly identified and corrected as it is a frequent contributor of reversible cardiac dysfunction.16,17 Calcium can be repleted either using calcium chloride at a dose of 10 mg/kg or calcium gluconate at a dose of 100 mg/kg. Centrallined administration is preferred for calcium chloride
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as extravasation of calcium can result in severe necrosis and tissue sloughing. Both preparations can be given as an intravenous push over 3–5 min or as an infusion over 1-h. The goal of therapy should be to maintain a normal ionized calcium concentration via intravenous calcium supplementation. The final cornerstone of this stage of resuscitation is administration of broad-spectrum antibiotics once appropriate cultures have been obtained. The initial antibiotics should be broad enough to cover the most likely pathogens and have adequate penetration into the presumed primary source of infection. Clinicians should be aware of specific susceptibility patterns in the community and institution to help guide initial therapy. Possible combinations of antibiotics include an extended spectrum penicillin or third- or fourth-generation cephalosporin or carbapenem ⫾ aminoglycoside ⫾ vancomycin. At the end of the initial 15-min period, if shock is not reversed a second peripheral intravenous catheter should be inserted and inotrope therapy started.
fold. Fluid-refractory shock is best managed with invasive hemodynamic monitoring, which in an uncooperative potentially coagulopathic patient is best accomplished by sedation and immobilization, requiring intubation and mechanical ventilation for optimal control. Intubation and mechanical ventilation is also an important intervention for any patient whose cardiovascular function is not rapidly stabilized with fluid and inotropes. Up to 40% of cardiac output may be needed to support the work of breathing and this can be unloaded by providing mechanical ventilation. In addition, the increased intrathoracic pressure provided by mechanical ventilation reduces left ventricular afterload, which may be beneficial to patients with a low cardiac index and high systemic vascular resistance. In patients with elevated pulmonary vascular resistance, ventilator-controlled mild hyperventilation can compensate for metabolic acidosis. Finally, in any patient with evidence of respiratory failure or impaired mental status, there should be no hesitation to proceed with intubation and the initiation of mechanical ventilation.
Time 15–60 min At time point 15 min, if shock is not reversed it is considered to be fluid refractory and inotropes should be started. The original guidelines published in 2002 recommended obtaining central venous access prior to starting therapy. It was found that mortality increased with delay in time to inotropic use due to lack of central venous access and subsequent guidelines recommended beginning this therapy via an intravenous or intraosseous catheter. Medications should be titrated to maintain adequate perfusion. At this point, central venous access and if needed, an airway, should be obtained. Ketamine and atropine are the recommended agents to use for sedation for these procedures. Ketamine is a central N-methyl-D-aspartate (NMDA) receptor blocker, which blocks nuclear factor κB transcription and reduces systemic interleukin-6 production. Ketamine does not affect the adrenal axis or cardiovascular stability, making it an ideal agent for use in patients in shock.18 Atropine is a competitive antagonist of the muscarinic acetylcholine receptor. It is administered prior to intubation for one of two reasons: either to block the action of the vagus nerve, which can be stimulated with direct laryngoscopy, especially in small infants or to counteract the sialogogue action of ketamine through its direct antimuscarinic action. Indications for intubation and mechanical ventilation in a patient in shock are several
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Cold Shock Cold shock is a consequence of poor cardiac output and is evidenced by poor peripheral perfusion with cool extremities, delayed capillary refill, and diminished or absent peripheral pulses. Low cardiac output (cold shock) has been shown to be associated with mortality in pediatric patients.19,20 Vasoactive agents suitable for the treatment of cold shock include dopamine and epinephrine administered into the central circulation.21 The dosing range for dopamine should fall within 5–9 mcg/kg/min; at this dose, it works as an inotrope to improve contractility.22 In instances when dopamine is ineffective, epinephrine in a dosing range of 0.05–0.3 mcg/kg/min should be used; in this dosing range, it acts predominantly as a β-adrenergic agonist with a resulting increase in heart rate and stroke volume. It should be noted that epinephrine stimulates gluconeogenesis and glycogenolysis and inhibits the action of insulin, leading to an increase in blood glucose. Epinephrine also promotes increased delivery of lactate to the liver (to be used as a substrate for glucose production), with a resulting increase in blood lactate concentration.
Warm Shock Warm shock is caused by low systemic venous resistance. Patients in this state appear overly well
Curr Probl Pediatr Adolesc Health Care, November/December 2013
perfused, with flash capillary refill, bounding peripheral pulses, and a flushed appearance. The vasoactive agent of choice for this state is centrally administered norepinephrine in a dosing range of 0.05–1 mcg/kg/min. Norepinephrine is a potent β-adrenergic agonist, which increases mean arterial pressure as a result of vasoconstriction with little change in heart rate.
pressure, cardiac output, and maintaining oxygen carrying capacity. At this point, the patient should be in an intensive care unit and invasive monitoring should guide further treatment. If not already done, a central venous catheter should be placed and a central venous pressure (CVP) recorded and trended. The optimal CVP for each patient will be dictated by their clinical condition. Although a CVP of 5–10 cm H2O is Time 60 min considered within normal range, some patients may require higher levels to maintain cardiac output. The first 60 min after the recognition of shock is Observing the relationship between the CVP and blood considered the “golden hour” during which time therapressure (i.e., when the CVP is 18 cm H2O, the patient pies need to be initiated to reverse the shock. Carcillo has normal BP for age, when it drops to 12 cm H2O the et al.5 showed an improved survival patient becomes hypotensive) in patients receiving 440 mL/kg of will guide the clinician as to what fluid in the first hour of treatment in a CVP a patient requires. Vasoacgroup of 34 patients presenting to the The first 60 minutes after tive agents and fluid should be emergency department in shock. Han the recognition of shock is titrated to maintain a normal et al.7 have shown that for every mean arterial pressure (MAP) considered the “golden additional hour of persistent shock, CVP, which range between 55 for hour” during which time there is a 42-fold increased odds of a term newborn and 65 for therapies need to be mortality in pediatric patients with patients who are 2 years of age septic shock. At time point 60 min, if initiated to reverse and older. Mixed venous oxygen the patient does not have evidence of the shock. saturation (SCVO2), an indirect reversal of shock, they fall into the indicator of the adequacy of carcategory of having catecholaminediac output to meet tissue metaresistant shock and hydrocortisone therapy should be bolic demand, should be checked periodically with a initiated if the patient is at risk for absolute adrenal goal of maintaining saturations 470%. Normal arterial insufficiency. A patient with purpura fulminans and oxygen saturation is 100% and mixed venous saturaWaterhouse–Friderichsen syndrome, one who has pretion is 470%. In concert with maintenance of cardiac viously received steroid therapies for chronic illness and output, hemoglobin concentration is an important one with pituitary or adrenal abnormalities are all at risk determinant of oxygen delivery. Maintaining a hemofor adrenal insufficiency. A peak cortisol concentratioglobin concentration 410 g/dL is of utmost imporn o18 mcg/dL obtained after corticotropin stimulation tance in a patient in shock.4,23 For patients with a is indicative of adrenal insufficiency. This test may be SCVO2 o70% adding a vasodilator with fluid loading helpful to perform in centers with the capability to obtain can improve oxygen delivery. Agents that can be used results in a timely fashion (i.e., 30 min or less) but in are nitrovasodilators, such as sodium nitroprusside, patients with catecholamine-resistant shock and risk nitroglycerine, and milrinone. The nitrovasodilators factors for adrenal insufficiency, steroids should not be recruit microcirculation and reduce ventricular afterwithheld due to lack of results. The dose of steroid can load, which allows better ventricular ejection and be titrated over a wide dosing range to achieve resolution overall improvement in cardiac output. Milrinone of shock, using between 2 and 50 mg/kg/d of hydroimproves contractility and lowers systemic vascular cortisone given as a continuous infusion or via interresistance by inhibiting type III phosphodiesterase, mittent dosing. The hydrocortisone should be weaned off which in turn increases intracellular cAMP by blocking as tolerated to minimize toxicity. its hydrolysis. It is not receptor mediated and is useful if adrenergic receptors are down regulated or desensitized. Because normal renal function is needed for Beyond the First Hour milrinone clearance, the dose should be lowered in patients with signs of renal insufficiency. Milrinone Beyond the first hour of treatment, the treatment goal has a long half-life compared to the other medications is to improve oxygen delivery by supporting blood
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and o6.0 L/min/m2, which has been associated with used to support blood pressure ( mean half-life 2.3 h) and can cause hypotension, which can be treated with the best outcomes in septic shock patient.22 For those norepinephrine or vasopressin. An alternative agent to patients not aided by these tools, extracorporeal consider is levosimendan, which exerts a positive membrane oxygenation (ECMO) should be considinotropic effect by increasing calcium sensitivity of ered. Survival rates in septic shock patients placed on myocytes by binding to cardiac troponin C in a ECMO are 73% for newborns and 39% for older calcium-dependent manner. It also has a vasodilatory children.26 effect by opening adenosine-triphosphate-sensitive Guidelines for the management of shock in children potassium channels in vascular smooth muscle. Thus, have been in effect for the last 10 years. They are time in the endotoxin-induced heart dysfunction of septic based and can be enacted in whatever setting shock is shock, levosimendan treats the first recognized. The interventions source of the problem.24 In are designed to quickly improve oxygen delivery through mainteinstances where these measures All practitioners who care nance of cardiac output and timely are not successful, vasopressin for pediatric patients are administration of antibiotics. Since should be added. Vasopressin is the original guidelines were puba peptide hormone that increases encouraged to become lished, two revisions have been peripheral vascular resistance via familiar with these made, but the content has remained the V1 receptors found on vasguidelines as they are clear, largely unchanged. Many studies cular smooth muscle of the systemic circulation. It has been concise and can save lives. have tested the recommendations of the original guidelines. There is shown to increase systemic vasample evidence that the guidelines cular resistance, mean arterial 25 are effective and do not cause harm.7,27–31 All practiblood pressure, and urine output in septic shock. There are some instances in which the patient remains tioners who care for pediatric patients are encouraged in shock despite all of the aforementioned intervento become familiar with these guidelines as they are tions. After initial assessment for correctable causes, clear, concise, and can save lives. such as pericardial effusions, pneumothoraces, and intra-abdominal hypertension, more advanced tools must be employed to guide therapy. Pulmonary artery References (PA) catheters can assist in the identification of 1. Carcillo JA, Fields AI, American College of Critical Care selective left ventricular dysfunction and can determine Medicine Task Force Committee Members. Clinical practice the relative contribution of right and left ventricular parameters for hemodynamic support of pediatric and neonatal work. The measured and derived values that are patients in septic shock. Crit Care Med 2002;30(6):1365–78. 2. Brierley J, Carcillo JA, Choong K, et al. Clinical practice obtained can allow the clinician to titrate medications parameters for hemodynamic support of pediatric and neonatal and interventions that affect preload, afterload, and septic shock: 2007 update from the American College of contractility and follow-up with subsequent PA cathCritical Care Medicine. Crit Care Med 2009;37(2):666–88. eter measurements to assess the effects of treatment. 3. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis Pulse index contour cardiac output catheters (PICCO) campaign: international guidelines for management of severe estimate global end-diastolic volume in the heart, sepsis and septic shock: 2012. Crit Care Med 2013;41(2): 580–637. extravascular lung water, and assess adequacy of 4. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed preload. PICCO catheters were developed as a lesstherapy in the treatment of severe sepsis and septic shock. invasive way to obtain much of the same information N Engl J Med 2001;345(19):1368–77. that PA catheters provide. The measurements from a 5. Carcillo JA, Davis AL, Zaritsky A. Role of early fluid PICCO catheter allow the clinician to assess cardiac resuscitation in pediatric septic shock. J Am Med Assoc 1991;266(9):1242–5. function and volume status and titrate therapies accord6. Kern JW, Shoemaker WC. Meta-analysis of hemodynamic ingly. Follow-up measurements are then obtained to optimization in high-risk patients. Crit Care Med 2002;30(8): evaluate treatment. Femoral artery thermodilution 1686–92. catheters and Doppler ultrasound can also aid in the 7. Han YY, Carcillo JA, Dragotta MA, et al. Early reversal of assessment of cardiac output. These devices can help pediatric-neonatal shock by community physicians is associguide therapy to achieve a goal cardiac index of 43.3 ated with improved outcome. Pediatrics 2003;112(4):793–9. 290
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8. Pollack MM, Ruttimann UE, Getson PR. Pediatric risk of mortality (PRISM) score. Crit Care Med 1988;16(11):1110–6. 9. Stoner MJ, Goodman DG, Cohen DM, et al. Rapid fluid resuscitation in pediatrics; testing the ACCM guidelines. Crit Care Med 2005;33:A68. 10. Zadrobilek E, Hackl W, Sporn P, Steinbereithner K. Effect of large volume replacement with balanced electrolyte solutions on extravascular lung water in surgical patients with sepsis syndrome. Intensive Care Med 1989;15(8):505–10. 11. Powell KR, Sugarman LI, Eskenazi AE, et al. Normalization of plasma arginine vasopressin concentrations when children with meningitis are given maintenance plus replacement fluid therapy. J Pediatr 1990;117(4):515–22. 12. Ngo NT, Cao XT, Kneen R, et al. Acute management of dengue shock syndrome: a randomized double-blind comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis 2001;32(2):204–13. 13. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomized controlled trials. Br Med J 1998;317(7153):235–40. 14. Oca MJ, Nelson M, Donn SM. Randomized trial of normal saline versus 5% albumin for the treatment of neonatal hypotension. J Perinatol 2003;23(6):473–6. 15. Lin JC, Carcillo JA. Increased glucose/glucose infusion rate ratio predicts anion gap acidosis in pediatric sepsis. Crit Care Med 2004;32(suppl 20):A5. 16. Cardenas-Rivero N, Chernow B, Stoiko MA, Nussbaum SR, Todres ID. Hypocalcemia in critically ill children. J Pediatr 1989;114(6):946–51. 17. Roberton NR, Smith MA. Early neonatal hypocalcaemia. Arch Dis Child 1975;50(8):604–9. 18. Yli-Hankala A, Kirvelä M, Randell T, Lindgren L. Ketamine anaesthesia in a patient with septic shock. Acta Anaesthesiol Scand 1992;36(5):483–5. 19. Pollack MM, Fields AI, Ruttimann UE. Sequential cardiopulmonary variables of infants and children in septic shock. Crit Care Med 1984;12(7):554–9. 20. Pollack MM, Fields AI, Ruttimann UE. Distributions of cardiopulmonary variables in pediatric survivors and nonsurvivors of septic shock. Crit Care Med 1985;13(6):454–9. 21. Perkin RM, Levin DL. Shock in the pediatric patient. Part II. Therapy. J Pediatr 1982;101(3):319–32.
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22. Ceneviva G, Pashcal JA, Eckstein J, et al. Hemodynamic support in fluid refractory pediatric septic shock. Pediatrics 1998;102:e19. 23. de Oliveira CF, de Oliveira DS, Gottschald AF, Moura JD, Costa GA, et al. ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation. Intensive Care Med 2008;34(6):1065–75. 24. Matejovic M, Krouzecky A, Radej J, Novak I. Successful reversal of resistant hypodynamic septic shock with levosimendan. Acta Anaesthesiol Scand 2005;49(1):127–8. 25. Liedel JL, Meadow W, Nachman J, Koogler T, Kahana MD. Use of vasopressin in refractory hypotension in children with vasodilatory shock: five cases and a review of the literature. Pediatr Crit Care Med 2002;3(1):15–8. 26. Skinner SC, Iocono JA, Ballard HO, et al. Improved survival in venovenous vs venoarterial extracorporeal membrane oxygenation for pediatric noncardiac sepsis patients: a study of the Extracorporeal Life Support Organization registry. J Pediatr Surg 2012;47(1):63–7. 27. Wills BA, Nguyen MD, Ha TL, et al. Comparison of the three fluid solutions for resuscitation in dengue shock. N Engl J Med 2005;353:877–89. 28. Maitland K, Pamba A, English M, et al. Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit. Clin Infect Dis 2005;40:538–45. 29. Ninis N, Phillips C, Bailey L, et al. The role of healthcare delivery on outcome of meningococcal disease in children: Case control study of fatal and non-fatal cases. Br Med J 2005;330:1475. 30. de Oliveira CF, de Oliveira DS, Gottschald AF, et al. ACCM/ PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation. Intensive Care Med 2008; 34:1065–75. 31. Karapinar B, Lin JC, Carcillo JA. ACCM guidelines use, correct antibiotic therapy, and immune suppressant withdrawal are associated with improved survival in pediatric sepsis, severe sepsis, and septic shock. Crit Care Med 2004; 32(12 suppl 3):A161.
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